Huntington’s research results in treatment advance

Treatment of Huntington’s disease may become
more targeted and individualised as a result of research at
the University of Auckland’s Centre for Brain
Research.

Scientists have for decades strived to
understand why Huntington’s disease, which is caused by a
single gene mutation, can produce such variable
symptoms.

Post-doctoral researcher, Dr Eric Kim with his
supervisor, Distinguished Professor Richard Faull, have
found that different Huntington’s disease symptoms are
characterised by cell loss in different functional regions
of the brain, suggesting a possible direction for developing
targeted therapies.

In patients with severe motor and
movement disorders, there was significant cell loss only in
the motor cortex, (a region that regulates movement). In
patients with severe behavioural and mood affected
disorders, they found the opposite – that there was
significant cell loss in the limbic cortex, (a region which
regulate mood and behaviour), and not in the motor
cortex.

“This is direct evidence to show the structural
or anatomical origins of the symptom variability in
Huntington’s disease, and shows why some people manifest
with different symptom profiles in Huntington’s
disease,” says Dr Kim, who was involved in this work over
the past four years. “It also showed us that every
individual Huntington’s disease patient is slightly
different in the way their symptoms show up in the
brain.”

“Even studies on a pair of identical twins
that share the same genetic background, show different
symptom profiles,” he says.

The study team used tissue
from the Centre’s Human Brain Bank and characterised 13
Huntington’s disease patients and compared it to 15 normal
control brains at the cellular level.It’s already
known from previous research over the past two decades that
Huntington’s disease is caused by a single gene mutation
that produces a mutant protein which forms aggregates within
the neurons. The formation of these aggregates is known to
cause an array of molecular changes that ultimately results
in overt clinical symptoms associated with Huntington’s
disease.

Although it is caused by a single gene, there are
major variations in the symptoms of Huntington’s disease.
The pattern of symptoms exhibited by each individual can
differ considerably and present as varying degrees of jerky
movements, mood and behavioural changes, and cognitive
decline such as memory loss.

Recent investigations have
focused on what the defective gene does to various
structures in the brain and understanding the relationship
between changes in the brain and the variable symptom
profiles in Huntington’s disease.

Analyses of
post-mortem human Huntington’s disease tissue suggest that
variation in clinical symptoms is strongly associated with
degeneration in two major regions of the brain, the striatum
of the basal ganglia and the cerebral cortex.

The brain
mass at the base of the brain – the basal ganglia – has
strong connections with the lining of the outer layer of the
brain – the cerebral cortex, says Dr Kim. The cerebral
cortex initiates signals that are interpreted by the basal
ganglia.

“There are already well validated studies that
the cerebral cortex and the basal ganglia are severely
affected in Huntington’s disease,” he says. “That
work is done using magnetic resonance imaging (MRI) with
researchers from Boston at the forefront of that
research.”The brains of Huntington’s disease
patients show severe atrophy in both the basal ganglia and
the cerebral cortex.

As MRIs can show the region of the
brain affected, but not what is happening at the cellular
level, another approach was needed to find the different
cell types involved in each of the disease
processes.

“We decided to characterise 13 Huntington’s
disease patient cases and compare them to 15 normal control
cases,” says Dr Kim. “We focussed our study on the motor
cortex for movement symptoms and the limbic cortex for mood
and behavioural symptoms.”

The study team worked with
psychologists, Dr Lynette Tippett and Virginia Hogg from the
University’s Department of Psychology, who did clinical
data analysis on the clinical symptom profiles for each
case.

“We divided the patient group between those who
had mainly behavioural symptoms and those with predominantly
motor symptoms, and found that there were major differences
in terms of cell loss in the motor cortex and limbic cortex,
“ he says.

“There, a major cell loss in the motor
cortex was only observed in the patient group with
predominant motor symptoms and a major cell loss in the
limbic cortex was only observed in the patient group with
mainly behavioural symptoms.”

“This suggests that our
own recent detailed quantitative study in the post-mortem
human Huntington’s disease brain has complemented and
expanded the neuroimaging studies by providing a cellular
basis of symptom variability in Huntington’s disease,”
says Dr Kim. At present, there are several treatment
strategies for Huntington’s disease under study.

These
include cell transplants, gene therapy, and approved drugs
to manage or alleviate the symptoms.

The research formed part of Dr Kim’s
doctorate that he has followed up in his post-doctoral
research studies.

The research was published in a highly
rated clinical neurology journal, the Annals of Neurology.
It was supported by a grant from the Health Research Council
of New Zealand, Neurological Foundation of New Zealand and
the Auckland Medical Research
Foundation.

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